PROJECT SUMMARY
Posttraumatic epilepsy (PTE) refers to chronic unprovoked seizures following traumatic brain injury (TBI),
and is a major clinical problem in both the military and civilian populations. Despite the importance of PTE,
the locus of where PTE develops relative to the site of head injury and thus the anatomy of development of
PTE in distributed brain networks is not well understood. Consequently, the physiological changes occurring
specifically in the PTE seizure focus underlying epilepsy have not been determined. Our long-term goal is
to identify mechanisms of PTE. The objective here is to determine the anatomic locus of PTE in the
controlled cortical impact (CCI) model of TBI and to determine underlying cellular, molecular, and
physiological alterations accompanying PTE. Our central hypothesis is that following CCI, localized
molecular changes that impair astrocytic function and divergent injury-induced microcircuit reorganization of
intratelencepalic (IT) and extratelencepalic (ET) Layer 5 pyramidal cells (L5PCs) and hippocampal CA1
pyramidal cells (HPCs) underlie emergence of seizure foci. By using multielectrode array (MEA)
electroencephalography (EEG) to define the seizure focus at various time points after CCI and comparing
the molecular, cellular and circuit alterations in electrographically defined seizure foci in PTE mice with
corresponding loci in seizure-free injured mice, we will identify the cellular and circuit changes and
electrographic markers that predict transition to PTE. First, we will define the anatomic locus and
electrographic biomarkers of PTE onset in the animal model of controlled cortical impact (CCI) using
multielectrode array (MEA) electroencephalography (EEG). Second, we will determine which cellular and
molecular changes in the seizure focus underlie the onset of PTE. Third, we will identify cell-type specific
changes in L5PC (IT and ET) and HPC physiology and compromises in astrocytic transporter function that
underlie emergence of seizure foci. These experiments are anticipated to have a positive impact by
elucidating the necessary and sufficient changes in the brain underlying PTE and identifying new cellular and
molecular targets for treatment.